Tuberous sclerosis complex (TSC), a genetic disorder that causes autism in about half of those affected, could stem from a defect in a basic system cells use to recycle their mitochondria, report scientists at Boston Children's Hospital.
Defects in mitophagy, or autophagy of mitochondria, have already been implicated in a number of neurological disorders such as Parkinson's disease and Alzheimer's disease. The scientists believe their findings open new treatment possibilities not just for TSC, but possibly for other forms of autism and some neurological disorders.
Mitochondria, the organelles responsible for cellular energy production and metabolism, constantly get recycled. Through a process known as autophagy ("self-eating"), cells literally digest their damaged or aging mitochondria, clearing the way for healthy replacements.
"We decided to use tuberous sclerosis, a genetically defined disorder that has a high incidence of autism, as a model to understand the role of mitochondrial dynamics," says Sahin.
Sahin, Ebrahimi-Fakhari and colleagues studied both rat neurons and patient-derived neurons affected by TSC and used live-cell imaging to examine the distribution and dynamics of mitochondria.
They found that the TSC neurons as a whole had more mitochondria, and in particular more fragmented and dysfunctional mitochondria. It shows that autophagy is defective in TSC.
The scientists further showed that two existing classes of drugs counter the defect: the epilepsy drug carbamazepine, and drugs known as mTOR inhibitors.
When treated, the dysfunctional neurons were able to clear damaged mitochondria and replenish healthy mitochondria, restoring a normal turnover.The mitochondria were replenished at presynaptic sites, where their presence is most critical.
"Our findings point to possible treatments for enhancing mitophagy for some neurodevelopmental and neurodegenerative diseases," says Sahin, who is also director of the Translational Neuroscience Center at Boston Children's and senior author on the paper.